Takeda's First-in-Class NAE Inhibitor Pevonedistat Fails to Meet Primary Endpoint in Phase 3 PANTHER Trial

Compiled & Translated丨newborn

On September 2, Takeda Pharmaceutical Company Limited announced that the Phase 3 PANTHER study (Pevonedistat-3001, NCT03268954) did not meet the pre-specified statistical significance for the primary endpoint of event-free survival (PFS).

It is reported that the trial was conducted in patients with high-risk myelodysplastic syndromes (HR-MDS), chronic myelomonocytic leukemia (CMML), and low-blast acute myeloid leukemia (LB-AML) to evaluate whether first-line treatment with pevonedistat in combination with azacitidine improves event-free survival (EFS) compared with azacitidine monotherapy. Events in this study were defined as death or transformation to AML in patients with HR-MDS or CMML, whichever occurred first, and death in patients with AML.

In the study, the safety profile of the pevonedistat plus azacitidine combination regimen was consistent with previously reported data. Full study data will be presented at an upcoming medical conference. Investigators in the study have been informed of the results to discuss potential implications with study participants. Takeda will work with investigators to determine the most appropriate course of action for each patient enrolled in the study.

Takeda's pevonedistat is a first-in-class NEDD8-activating enzyme (NAE) inhibitor that induces cancer cell death by disrupting protein homeostasis. In Phase 2 studies of patients with HR-MDS, higher-risk CMML (HR-CMML), and AML, as well as in a Phase 1 study of patients with AML, pevonedistat in combination with azacitidine has demonstrated promising clinical activity.

In late July 2020, the U.S. FDA granted Breakthrough Therapy Designation to pevonedistat for the treatment of patients with higher-risk myelodysplastic syndromes (HR-MDS). Results from the Phase 2 Pevonedistat-2001 study demonstrated that pevonedistat in combination with azacitidine was superior to azacitidine monotherapy across multiple efficacy endpoints in HR-MDS, including prolonged overall survival (23.9 months vs. 19.1 months), prolonged progression-free survival (20.2 months vs. 14.8 months), and an improved complete response rate (52% vs. 27%).

According to the announcement released by Takeda at the time, pevonedistat has the potential to become the first novel therapeutic option for HR-MDS in over a decade, expanding treatment options that have thus far been limited to hypomethylating agent (HMA) monotherapy.

A search of the US clinical trials database (clinicaltrials.gov) reveals that, in addition to the Phase 3 PANTHER study, Takeda is also evaluating pevonedistat in combination with azacitidine and azacitidine monotherapy for the treatment of patients with AML who are unfit for standard chemotherapy in the Phase 3 PEVOLAM study.

Furthermore, the company is also evaluating multiple combination regimens of pevonedistat in several Phase 2 clinical trials, including: pevonedistat + venetoclax + azacitidine for adult patients with AML who are ineligible for intensive chemotherapy; pevonedistat + decitabine + cedazuridine for adult patients with HR-MDS; pevonedistat + Keytruda for dMMR/MSI-H metastatic or locally advanced unresectable solid tumors; and pevonedistat + chemotherapy for mesothelioma and non-small cell lung cancer, among others.

Source: Takeda Provides Update on Phase 3 PANTHER (Pevonedistat-3001) Trial